Integrin is a transmembrane glycoprotein complex of a heterodimer which intermediates cell adhesion and signal transduction process, and comprises an α-subunit and a β-subunit. Relative affinity and specificity for ligand binding are determined by various combination of various α-subunits and β-subunits.
Integrin αvβ3 and αvβ5 are expressed in many cell types, and have been shown to intermediate not only osteoclast adhesion to bone matrix, but also some biologically related processes such as migration, adhesion or proliferation, etc. of vascular smooth muscle cell, tumor cell and endothelial cell, etc. In particular, it has been suggested that it plays a role in various kinds of states and disease states including tumor metastasis, growth of solid tumors (neoplasia), osteoporosis, Paget's disease, humoral hypercalcemia of malignancy, osteopenia, angiogenesis including tumor angiogenesis, arthritis including rheumatoid arthritis, psoriasis and migration of smooth muscle cell (for example, restenosis, arteriosclerosis).
Integrin αvβ6 plays an important part in physiological process and diseases (for example, inflammation, wound healing and tumor) to which epithelial cell relates. In particular, it has been known that the expression of it is increased in lung, skin, kidney, liver, uterus, etc., at the time of sexual cycles or tissue damage due to inflammation, and considered to relate to inflammation, fibrosis, etc. of these internal organs through control of inflammatory cell or cytokine such as TGF-β, etc.
With regard to tumor and fibrosis, not only integrin αvβ6, but also integrin αvβ3 relates thereto, so that to inhibit both of the integrins can be considered to be useful for suppression of tumor and fibrosis. (see Non-Patent Literature 1 to 3)
Heretofore, benzazepinone compounds similar to the compounds of the present invention have been disclosed, and it has been known that these compounds have integrin αvβ3 and αvβ5 inhibitory activity (see Patent Literatures 1 to 8). However, it cannot be said that sufficient effects can be obtained in the points of medicinal efficacy, pharmacokinetics, etc. Also, it has not been specifically disclosed that these compounds have integrin αvβ6 inhibitory activity.
Accordingly, it has been desired to develop non-peptide series low molecular weight compound having further excellent αv integrin receptor antagonistic activity in efficacy, pharmacodynamic characteristics and pharmacokinetic characteristics such as oral bioavailability and duration, etc. Moreover, in either of the above-mentioned literatures, there is no concrete disclosure about a benzazepinone compound having an imidazole ring structure which is ring-fused to a side chain of the benzazepine ring according to the compound of the present invention.    [Non-Patent Literature 1] Cell, 96, 319 (1999)    [Non-Patent Literature 2] J. Med. Chem., 45, 1045 (2002)    [Non-Patent Literature 3] Mol. Cell. Biol., 27, 4444 (2007)    [Patent Literature 1] WO 96/00574A    [Patent Literature 2] WO 96/00730A    [Patent Literature 3] WO 98/14192A    [Patent Literature 4] WO 98/15278A    [Patent Literature 5] WO 99/06049A    [Patent Literature 6] WO 99/15170A    [Patent Literature 7] WO 99/15178A    [Patent Literature 8] WO 02/90325A